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5.41 Gestational Hypertension

This study has demonstrated that circulating plasm a ADM A levels fall during

healthy, normotensive pregnancy. The reason for these changes was not investigated, but

could reflect changes in the rate o f ADM A synthesis or metabolism, its release from cells

or re-uptake into cells (Tickling et al, 1993; M acAllister et al, 1996a; Leiper et al, 2002).

Circulating ADM A levels might also have fallen secondary to the haemodynamic

changes o f healthy pregnancy. These include a 40% increase in plasm a volume (Brown and

Gallery, 1994) and 50% increase in glomerular filtration rate (GFR) (Sturgiss et al, 1994). Changes in haem atocrit did not however correlate with circulating ADM A concentration in

pregnancy (Holden et al, 1998) and in this study neither did creatinine clearance correlate

with ADM A levels. Creatinine clearance did however correlate with circulating levels o f the inactive isomer SDMA. Although ADM A accumulates in plasm a o f patients with renal

failure, the accumulation o f SDMA is several-fold higher (M acAllister et al, 1996b).

SDMA is not m etabolized like its active isomer ADM A, but id cleared by renal excretion

(M acAllister et al, 1996a). It would therefore seem most likely that during healthy

pregnancy, the metabolism o f ADM A is increased. The enzyme DDAH is a likely

candidate as it co-localises to sites o f NOS expression, including vascular endothelial cells

and placenta (Kimoto et al, 1995).

In Chapter 3, increased NOS activity was shown to play a role in the peripheral

vasodilatation o f healthy pregnancy. A gestational fall in plasm a ADM A concentration is

consistent w ith that finding. In rat pregnancy, the blunted pressor response to exogenous

angiotensin II (A ll) can be reversed by NOS inhibition (Abekas and Sibai, 1992). The

increased sensitivity to A ll in women destined to develop pre-eclam psia (Gant et al, 1974).

It is possible that low ADM A levels in normotensive pregnancy facilitate increased NOS

activity, which results in an attenuated pressor response to A ll and that elevated ADMA

levels in women w ith pre-eclampsia inhibits NOS activity and increases maternal

sensitivity to AIL

Pre-eclampsia is a plasma volume contracted state often associated with a reduction

in GFR, but for the reasons stated above, it is unlikely that either o f these haemodynamic

changes play a m ajor role towards the elevation o f plasm a ADM A levels in pre-eclampsia.

Increased circulating ADM A may be responsible for constricting the utero-placental

circulation and further compromising placental perfusion. Decreased placental perfusion is

a common observation in women with pre-eclampsia (W illiams and de Swiet, 1997) and may lead to a reduction in placental DDAH synthesis and consequently higher circulating

levels o f ADMA. DDAH activity can also be decreased by oxidised low-density lipoprotein

(LDL) and the pro-inflammatory cytokine TN F-a, leading to a rise in ADM A levels (Ito et

al, 1999). Both oxidized LDL and T N F -a levels are increased in pre-eclampsia (Uotila et

al, 1998; Williams et al, 1999). Further studies on placental activity o f DDAH would need

to clarify this issue.

Inhibition o f N OS by ADM A is competitively reversed by L-arginine (Vallance et

al, 1992). During healthy pregnancy, plasm a L-arginine levels fall, but are five fold lower

in women with pre-eclam psia (D ’Aniello et al, 2001). The relationship between plasma and

intracellular L-arginine is unclear, but it is likely that low circulating L-arginine levels

would enhance the inhibitory effect o f ADM A on NOS activity.

w omen rather than to pre-eclamptic women. This observation supports the phenotypic

differences between PIH and pre-eclampsia, where the former tends to be a high cardiac

output state w ith a large placenta and the latter tends to be a low cardiac output state with a

small placenta (Bosio et al, 1999). Women with PIH with a large placenta w ould be

expected to synthesise more DDAH and consequently have low er circulating ADM A

levels, similar to those found in women with normotensive pregnancies.

5.42 Fetal - Amniotic Fluid Circulation

In this study the concentration o f ADM A in amniotic fluid increased as pregnancy

progressed. In one human subject (mother and fetus) ADM A levels were shown to be

higher in fetal bladder than in amniotic fluid, which suggests that the fetal kidney, like the

adult kidney, excretes ADMA. This observation is supported by the results from pregnant

sheep that show a similar gradient o f ADM A concentration from fetal urine to amniotic

fluid as in humans. As the fetal kidney makes the greatest contribution to the composition

o f amniotic fluid (Lind, 1981), the increasing ADMA concentration may be influential on

neighbouring systems that utilize the L-arginine - NOS pathway.

By 20 weeks gestation uterine quiescence is m ediated by increased expression o f

inducible nitric oxide synthase (NOS-II) (Bansal et al, 1997). N OS-II activity falls at term

and m ay therefore allow stimulants o f uterine muscle to act unopposed for initiation o f

labour (Bansal et al, 1997; Wray, 1993). The results from this study are compatible with

the increasingly mature fetal kidney excreting ever more ADM A into amniotic fluid, until

eventually the concentration is high enough to inhibit myométrial NOS-II. This system may

be an exam ple o f fetal maturity dictating the onset o f labour. Further studies investigating

onset o f labour. The precise trigger to human labour has yet to be established, but is likely

to be a complex, multi-faceted system.

Nitric oxide also plays an important role in reducing pulm onary vascular resistance

(Rairigh et al, 2001). The fetal pulm onary circulation is vasoconstricted throughout

pregnancy. Oxygenated blood from the placenta is shunted from the right to left side o f the

fetal heart, bypassing the lungs. During pregnancy the fetal lungs are bathed in amniotic

fluid. At the mom ent o f birth, fetal pulm onary vascular resistance falls rapidly and

pulm onary blood flow increases 8-10 fold (Rudolph, 1979). It is possible that ADMA

within inhaled amniotic fluid keeps the fetal pulmonary arteries vasoconstricted, but when

amniotic fluid is expressed from the lungs at birth, pulm onary NOS is no longer inhibited

and pulm onary vascular resistance falls.

Further studies are necessary to clarify the role o f ADM A as a trigger for labour and

as a vasoconstrictor o f the fetal pulmonary vasculature in utero. Pathological changes to the metabolism o f L-arginine - NO- ADM A pathway may be responsible for pre-term labour

CHAPTER 6

THE ROLE OF PERIVASCULAR NERVES IN THE